Stanniocalcin 1 reversely correlates with checkpoint therapy efficacy

Significance 

Immune checkpoint-based therapy manifests unprecedented success against cancer through revitalizing and boosting T cell responses. However, the majority of patients with cancer do not respond to immune checkpoint therapy.

A deeper understanding of complex interactions between different immune cell subsets and tumor cells in the tumor microenvironment is crucial for dissecting intrinsic and adaptive immune resistance mechanisms. This will result in developing rationalized combinatorial therapeutic approaches and identifying potential novel targets.

To explore tumor-intrinsic immune resistance mechanisms in the tumor microenvironment in patients with defined immune checkpoint therapy responsiveness, we have analyzed the transcriptomes of two datasets in patients with melanoma treated with checkpoint therapy. Our goals are to explore a potential correlation between specific unknown gene transcripts in tumor cells and patient therapeutic responses to both PD-1 and CTLA-4 blockade in different patient cohorts, and subsequently elucidate how these gene(s) alter cancer immunity and immunotherapy efficacy. stanniocalcin-1 (STC1) is reported as a hormone-like protein and may mediate multiple biological activities. Nonetheless, its receptor and interaction partners, the mechanism(s) of action, and the potential importance of STC1 to tumor immunity remain unknown. Using several preclinical models and gain- and loss-of-function studies, we have demonstrated that tumor STC1 affected tumor immunity and tumor response to immunotherapy.

University of Michigan School of Medicine researchers led by Professor Marcin Cieslik discovered that tumor STC1 reversely correlates with checkpoint therapy efficacy in patients with cancer and is associated with poor patient survival across multiple cancer types. The research work is now published in the Journal Cancer Cell.

It was an unexpected discovery that started with an analysis of more than 1,000 genes. The question: why game-changing cancer immunotherapy treatments work for only a fraction of patients. The analysis shone a light on one that popped up repeatedly in patients and mouse models that did not respond to immune checkpoint therapy: stanniocalcin-1, a glycoprotein whose role in both tumors and immunology is largely unknown.

By following the trail from this surprising thread, a University of Michigan Rogel Cancer team uncovered how stanniocalcin-1, or STC1, works inside the cell to block a cellular “eat-me” signal that typically triggers the immune system to produce T cells to fight the tumor.  They believe STC1 is a checkpoint inside the cell. It’s an eat-me blocker it blocks macrophages and dendritic cells to eat dying or dead cancer cells. According to the author the STC1 pathway can be targeted, which would release the blocked eat-me signal.

The authors were drawn to STC1 in part because so little was known about its role in cancer. This provided a potentially interesting opportunity, but also some difficulty as they had to start at the very beginning to understand whether STC1 was causing the poor immune response or whether it was just a bystander.

They embarked on a lengthy process, first showing that STC1 was linked with low activation of T cells and worse survival in melanoma patients treated with immunotherapy. They checked against the Cancer Genome Atlas database and found high levels of STC1 tied to worse survival in 10 different cancer types. The finding also panned out in mouse models.

From there, the researchers used mouse models to show that STC1 within tumors was dampening the anti-tumor T cell response by impairing the antigen presenting cells, which are essential for triggering T cells. They showed that tumor STC1 was stopping the process of macrophages, a type of antigen presenting cell, from eating dying tumor cells a process key to presenting antigen to T cells and activating them.

Specifically, the tumor STC1 traps a key eat-me signal called calreticulin, or CRT. Without sufficient surface CRT, the macrophages won’t efficiently eat the dead tumor cells. Unblock the CRT and it unblocks this process. This suggests that targeting the interaction between STC1 and CRT might be a path toward making immunotherapy more effective.

It’s an unusual mechanism. Most immune checkpoint therapies are based on direct surface interactions with T cells. What we are talking about is before anything has happened. Before the T cells were activated, the tumors have already implemented strategies so they cannot be captured. This may be why some patients are resistant to immunotherapy: their tumors express too much STC1. When you block the eat-me signal, the antigen presenting cells cannot do their job.

Targeting the STC1 and CRT interaction inside the cell is trickier than if it were on the cell surface. It means a typical antibody approach will not work. Instead, the research team are investigating whether they can develop a small compound that would penetrate the cell and interfere with the STC1-CRT interaction.

Stanniocalcin 1 reversely correlates with checkpoint therapy efficacy - Medicine Innovates
The interaction between STC1 and calreticulin. Credit: University of Michigan Rogel Cancer Center

About the author

Marcin Cieslik, Assistant Professor of Pathology and Computational Medicine and Bioinformatics and member of the Michigan Center for Translational Pathology (MCTP), received an award from Bristol-Myers Squibb (BMS) for the project entitled, Identification of novel therapeutic vulnerabilities across immunophenotypes of refractory and metastatic tumors. This award provides two years of funding.

Dr. Cieslik will be working with BMS colleague Dr. Rohit Malik (former MCTP researcher) as part of a collaborative research program, to identify novel molecular subtypes of cancers and their predicted drug-sensitivity characteristics. They hypothesize that differences in outcomes between metastatic patients are partially explained by their associations with distinct immunological subtypes, and that progression from primary to metastatic disease is associated with a shift towards immune evasive genetic subtypes.

The overarching objective of this research is to: (i) comprehensively characterize immune phenotypes of metastatic tumors, (ii) to identify genomic features associated with immune cell infiltration, and (iii) to determine whether immune genotypes or phenotypes are associated with outcomes. They also propose to leverage DepMap in order to identify cell-line avatars, and potential treatment opportunities, for immune evasive subtypes.

Reference

H. Lin, Ilona Kryczek, Shasha Li, M. Green, A. Ali, Reema Hamasha, S. Wei, Linda Vatan, W. Szeliga, S. Grove, Xiong Li, J. Li, W. Wang, Yijian Yan, J. E. Choi, G. Li, Yingjie Bian, Ying Xu, J. Zhou, Jiali Yu, H. Xia, W. Wang, A. Alva, A. Chinnaiyan, Marcin Cieślik, W. Zou. Stanniocalcin 1 is a phagocytosis checkpoint driving tumor immune resistance. Cancer Cell, 28 January 2021

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